This invention relates to a 9-acylamino-tetrahydroacridine derivative which is novel and available and which improves disfunction of cholinergic neurons, its optical antipode or pharmaceutically acceptable acid addition salt thereof, and a memory enhancing agent containing these compounds as an active ingredient.
As a therapeutic method of various memory disorder characterized by decreasing in cholinergic nervous function such as Alzheimer's disease, there exists an attempt to heighten a content of acetylcholine in brain using an acetylcholine esterase inhibitor. For example, an investigation using physostigmine has been reported in Neurology, Vol. 8, p. 377 (1978). Further, in publications of Japanese Provisional Patent Publications No. 148154/1986, No. 141980/1988, No. 166881/1988, No. 203664/1988, No. 225358/1988, No. 238063/1988 and No. 239271/1988; EP-A-268,871; and International Provisional Patent Publication No. 88/02256, there have been reported that specific 9-amino-tetrahydroacridine derivatives have acetylcholine esterase inhibiting functions and are effective for therapy of Alzheimer's disease. Also, there has been reported by Summers in "The New England Journal of Medicine, Vol. 315, p. 1241 (1986)" that 9-amino-1,2,3,4-tetrahydroacridine (tacrine) is effective to human Alzheimer's disease in combination with use of lecithin. However, the above methods involve problems that sufficient improvement has not yet accomplished or adverse reaction is caused whereby new therapeutic method has been desired.
On the other hand, as examples of known 9-acylamino-tetrahydroacridine, 9-acetylamino-tetrahydroacridine is described in "Journal of Chemical Society, p. 634 (1947)", and also 9-chloroacetylamino-tetrahydroacridine and 9- diethylaminoacetylamino-tetrahydroacridine are described in "Chem. listy, Vol. 51, p. 1056 (1957)" and also described that the latter has local anesthetic function. Further, in "Journal of Medicinal Chemistry, Vol. 18, p. 1056 (1975)", relationships in structural activity of acetylcholine esterase inhibiting function of 9-amino-tetrahydroacridine are described, and also described are activities of 9-acetylamino-tetrahydroacridine and 9-benzoylaminotetrahydroacridine become 1/1000 to that of 9-amino-tetrahydroacridine. Moreover, in the aforesaid patent publications (Japanese Provisional Patent Publications No. 166881/1988, No. 203664/1988, No. 225358/1988, No. 238063/1988 and No. 239271/1988), while 9-acylamino-tetrahydroacridine derivatives have been claimed, there is neither described in each of the publications concerning concrete synthetic examples nor pharmacological activities of the compounds having 9-acylamino group.